Date of Award
Doctor of Philosophy (PhD)
Despite enormous efforts, cancer remains a leading cause of morbidity and mortality world-wide. The main challenges currently facing cancer therapy include lack of adequate tumor targeting, failure to treat hypoxic tumor cells, and induction therapy resistant tumors. A solution to these limitations can be found in photodynamic therapy (PDT) which combines light and light activatable compounds, photosensitizers (PSs), to produce cytotoxic reactive oxygen species (ROS) to damage tumor tissue. This creates a spatiotemporal therapeutic effect, where cell damage only occurs at the intersection of the PS and light. PDT can treat tumors through unique mechanisms which reduce induction of tumor resistance. Although PDT has had clinical success in treating skin cancer and macular degeneration, it has yet to be a widely adopted or accepted therapy.
In this dissertation, we lay the groundwork for a new PDT strategy which systematically addresses and optimizes each aspect of PDT. To overcome the limitation of PDT to treat hypoxic tumors, we developed a novel nano-photosensitizer, TiO2-N3, that produces cytotoxic ROS even under hypoxic conditions. Next, to determine the optimal intracellular target for TiO2-N3, we compared the therapeutic outcome of ROS generated in endosomes, lysosomes, mitochondria, and ER. We identified the ER as the organelle most sensitive to ROS damage and therefore the optimal intracellular target for TiO2-N3. Finally, to deliver TiO2-N3 to tumors in vivo, we developed two tumor targeting agents, both of which are equipped with near-infrared fluorophores for whole body imaging. This work has laid the foundation for a novel PDT strategy by overcoming issues that have limited the clinical adoption of PDT.
Mikhail Y. Berezin, Joseph P. Culver, Kristen M. Naegle, Lihong V. Wang,